NKp44-Derived Peptide Binds Proliferating Cell Nuclear Antigen and Mediates Tumor Cell Death
Proliferating cell nuclear antigen (PCNA) is considered as a hub protein and is a key regulator of DNA replication, repair, cell cycle control, and apoptosis. PCNA is overexpressed in many cancer types, and PCNA overexpression is correlated with cancer virulence. Membrane-associated PCNA is a ligand...
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doaj-c70129e8d84e4ab28ebedd562a2d6a462020-11-25T01:05:56ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-05-01910.3389/fimmu.2018.01114360874NKp44-Derived Peptide Binds Proliferating Cell Nuclear Antigen and Mediates Tumor Cell DeathAvishai Shemesh0Avishai Shemesh1Kiran Kundu2Kiran Kundu3Refael Peleg4Rami Yossef5Irena Kaplanov6Susmita Ghosh7Yana Khrapunsky8Orly Gershoni-Yahalom9Orly Gershoni-Yahalom10Tatiana Rabinski11Adelheid Cerwenka12Roee Atlas13Angel Porgador14Angel Porgador15The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, IsraelNational Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, IsraelNational Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, IsraelNational Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, IsraelSurgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesThe Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, IsraelNational Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, IsraelNational Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, IsraelInnate Immunity Group, German Cancer Research Center and Medical Faculty Mannheim, Heidelberg University, Heidelberg, GermanyNational Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, IsraelNational Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, IsraelProliferating cell nuclear antigen (PCNA) is considered as a hub protein and is a key regulator of DNA replication, repair, cell cycle control, and apoptosis. PCNA is overexpressed in many cancer types, and PCNA overexpression is correlated with cancer virulence. Membrane-associated PCNA is a ligand for the NKp44 (NCR2) innate immune receptor. The purpose of this study was to characterize the PCNA-binding site within NKp44. We have identified NKp44-derived linear peptide (pep8), which can specifically interact with PCNA and partly block the NKp44–PCNA interaction. We then tested whether NKp44-derived pep8 (NKp44-pep8) fused to cell-penetrating peptides (CPPs) can be employed for targeting the intracellular PCNA for the purpose of anticancer therapy. Treatment of tumor cells with NKp44-pep8, fused to R11-NLS cell-penetrating peptide (R11-NLS-pep8), reduced cell viability and promoted cell death, in various murine and human cancer cell lines. Administration of R11-NLS-pep8 to tumor-bearing mice suppressed tumor growth in the 4T1 breast cancer and the B16 melanoma in vivo models. We therefore identified the NKp44 binding site to PCNA and further developed an NKp44-peptide-based agent that can inhibit tumor growth through interfering with the function of intracellular PCNA in the tumor cell.https://www.frontiersin.org/article/10.3389/fimmu.2018.01114/fullNKp44peptide screencell-penetrating peptideproliferating cell nuclear antigencancer therapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Avishai Shemesh Avishai Shemesh Kiran Kundu Kiran Kundu Refael Peleg Rami Yossef Irena Kaplanov Susmita Ghosh Yana Khrapunsky Orly Gershoni-Yahalom Orly Gershoni-Yahalom Tatiana Rabinski Adelheid Cerwenka Roee Atlas Angel Porgador Angel Porgador |
spellingShingle |
Avishai Shemesh Avishai Shemesh Kiran Kundu Kiran Kundu Refael Peleg Rami Yossef Irena Kaplanov Susmita Ghosh Yana Khrapunsky Orly Gershoni-Yahalom Orly Gershoni-Yahalom Tatiana Rabinski Adelheid Cerwenka Roee Atlas Angel Porgador Angel Porgador NKp44-Derived Peptide Binds Proliferating Cell Nuclear Antigen and Mediates Tumor Cell Death Frontiers in Immunology NKp44 peptide screen cell-penetrating peptide proliferating cell nuclear antigen cancer therapy |
author_facet |
Avishai Shemesh Avishai Shemesh Kiran Kundu Kiran Kundu Refael Peleg Rami Yossef Irena Kaplanov Susmita Ghosh Yana Khrapunsky Orly Gershoni-Yahalom Orly Gershoni-Yahalom Tatiana Rabinski Adelheid Cerwenka Roee Atlas Angel Porgador Angel Porgador |
author_sort |
Avishai Shemesh |
title |
NKp44-Derived Peptide Binds Proliferating Cell Nuclear Antigen and Mediates Tumor Cell Death |
title_short |
NKp44-Derived Peptide Binds Proliferating Cell Nuclear Antigen and Mediates Tumor Cell Death |
title_full |
NKp44-Derived Peptide Binds Proliferating Cell Nuclear Antigen and Mediates Tumor Cell Death |
title_fullStr |
NKp44-Derived Peptide Binds Proliferating Cell Nuclear Antigen and Mediates Tumor Cell Death |
title_full_unstemmed |
NKp44-Derived Peptide Binds Proliferating Cell Nuclear Antigen and Mediates Tumor Cell Death |
title_sort |
nkp44-derived peptide binds proliferating cell nuclear antigen and mediates tumor cell death |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2018-05-01 |
description |
Proliferating cell nuclear antigen (PCNA) is considered as a hub protein and is a key regulator of DNA replication, repair, cell cycle control, and apoptosis. PCNA is overexpressed in many cancer types, and PCNA overexpression is correlated with cancer virulence. Membrane-associated PCNA is a ligand for the NKp44 (NCR2) innate immune receptor. The purpose of this study was to characterize the PCNA-binding site within NKp44. We have identified NKp44-derived linear peptide (pep8), which can specifically interact with PCNA and partly block the NKp44–PCNA interaction. We then tested whether NKp44-derived pep8 (NKp44-pep8) fused to cell-penetrating peptides (CPPs) can be employed for targeting the intracellular PCNA for the purpose of anticancer therapy. Treatment of tumor cells with NKp44-pep8, fused to R11-NLS cell-penetrating peptide (R11-NLS-pep8), reduced cell viability and promoted cell death, in various murine and human cancer cell lines. Administration of R11-NLS-pep8 to tumor-bearing mice suppressed tumor growth in the 4T1 breast cancer and the B16 melanoma in vivo models. We therefore identified the NKp44 binding site to PCNA and further developed an NKp44-peptide-based agent that can inhibit tumor growth through interfering with the function of intracellular PCNA in the tumor cell. |
topic |
NKp44 peptide screen cell-penetrating peptide proliferating cell nuclear antigen cancer therapy |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2018.01114/full |
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